Abstract
BACKGROUND AND PURPOSE: We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures. EXPERIMENTAL APPROACH: HEK293A cells expressing either human type 1 cannabinoid (CB(1) ) receptors or CB(2) receptors were treated with CBD or CBD-DMH with or without the CB(1) and CB(2) receptor agonist CP55,940, CB(1) receptor allosteric modulator Org27569 or CB(2) receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB(1) or CB(2) receptors, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB(1) receptors. KEY RESULTS: At CB(1) receptors, CBD was a negative allosteric modulator (NAM), and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB(1) receptors (5TGZ) but shared a binding site with CP55,940 in the agonist-bound model of CB(1) receptors (5XRA). The binding site for CBD-DMH in the CB(1) receptor models overlapped with CP55,940 and Org27569. At CB(2) receptors, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation but a NAM of βarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB(2) receptor models that was separate from CBD-DMH. CONCLUSION AND IMPLICATIONS: The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB(1) and CB(2) receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB(1) and CB(2) receptors. LINKED ARTICLES: This article is part of a themed section on 8(th) European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.